Vitamin D the Blood Pressure Regulation - Crohn’s disease vitamin D deficiency

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Micronutrient Information CenterVitamin DVitamin D is a fat-soluble vitamin that is essential for maintaining normal calcium metabolism (1). Vitamin D3 (cholecalciferol) can be synthesized by humans in the skin upon exposure to ultraviolet-B (UVB) radiation from sunlight, or it can be obtained from the diet. Plants synthesize ergosterol, which is converted to vitamin D2 (ergocalciferol) by ultraviolet light. Vitamin D2 is less active in birds than vitamin D3 and may also be less active in humans (2). When exposure to UVB radiation is insufficient for the synthesis of adequate amounts of vitamin D3 in the skin, adequate intake of vitamin D from the diet is essential for health.FunctionActivation of Vitamin DVitamin D itself is biologically inactive, and it must be metabolized to its biologically active forms. After it is consumed in the diet or synthesized in the epidermis of skin, vitamin D enters the circulation and is transported to the liver. In the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. Increased exposure to sunlight or increased dietary intake of vitamin D increases serum levels of 25(OH)D, making the serum 25(OH)D concentration a useful indicator of vitamin D nutritional status. In the kidney, the 25(OH)D3-1-hydroxylase enzyme catalyzes a second hydroxylation of 25(OH)D, resulting in the formation of 1alpha,25-dihydroxyvitamin D [1,25(OH)2D]—the most potent form of vitamin D. Most of the physiological effects of vitamin D in the body are related to the activity of 1,25(OH)2D (3). Mechanisms of Action Many of the biological effects of 1,25(OH)2D are mediated through a nuclear transcription factor known as the vitamin D receptor (VDR) (4). Upon entering the nucleus of a cell, 1,25(OH)2D associates with the VDR and promotes its association with the retinoic acid X receptor (RXR). In the presence of 1,25(OH)2D the VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs) and initiates a cascade of molecular interactions that modulate the transcription of specific genes. More than 50 genes in tissues throughout the body are known to be regulated by 1,25(OH)2D (5).Calcium BalanceMaintenance of serum calcium levels within a narrow range is vital for normal functioning of the nervous system, as well as for bone growth and maintenance of bone density. Vitamin D is essential for the efficient utilization of calcium by the body (1). The parathyroid glands sense serum calcium levels and secrete parathyroid hormone (PTH) if calcium levels drop too low (diagram). Elevations in PTH increase the activity of the 25(OH)D3-1-hydroxylase enzyme in the kidney, resulting in increased production of 1,25(OH)2D. Increasing 1,25(OH)2D production results in changes in gene expression that normalize serum calcium by 1) increasing the intestinal absorption of dietary calcium, 2) increasing the reabsorption of calcium filtered by the kidneys, and 3) mobilizing calcium from bone when there is insufficient dietary calcium to maintain normal serum calcium levels. Parathyroid hormone and 1,25(OH)2D are required for these latter two effects (6).Cell DifferentiationCells that are dividing rapidly are said to be proliferating. Differentiation results in the specialization of cells for specific functions. In general, differentiation of cells leads to a decrease in proliferation. While cellular proliferation is essential for growth and wound healing, uncontrolled proliferation of cells with certain mutations may lead to diseases like cancer. The active form of vitamin D, 1,25(OH)2D, inhibits proliferation and stimulates the differentiation of cells (1). ImmunityVitamin D in the form of 1,25(OH)2D is a potent immune system modulator. The vitamin D receptor (VDR) is expressed by most cells of the immune system, including T cells and antigen-presenting cells, such as dendritic cells and macrophages (7). Under some circumstances, macrophages also produce the 25(OH)D3-1-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2D (8). There is considerable scientific evidence that 1,25(OH)2D has a variety of effects on immune system function, which may enhance innate immunity and inhibit the development of autoimmunity (9).Insulin SecretionThe VDR is expressed by insulin-secreting cells of the pancreas, and the results of animal studies suggest that 1,25(OH)2D plays a role in insulin secretion under conditions of increased insulin demand (10). Limited data in humans suggest that insufficient vitamin D levels may have an adverse effect on insulin secretion and glucose tolerance in type 2 diabetes (noninsulin-dependent diabetes mellitus; NIDDM) (11-13).Blood Pressure RegulationThe renin-angiotensin system plays an important role in the regulation of blood pressure (14). Renin is an enzyme that catalyzes the cleavage (splitting) of a small peptide (Angiotensin I) from a larger protein (angiotensinogen) produced in the liver. Angiotensin converting enzyme (ACE) catalyzes the cleavage of angiotensin I to form angiotensin II, a peptide that can increase blood pressure by inducing the constriction of small arteries and by increasing sodium and water retention. The rate of angiotensin II synthesis is dependent on renin (15). Research in mice lacking the gene encoding the VDR indicates that 1,25(OH)2D decreases the expression of the gene encoding renin through its interaction with the VDR (16). Since inappropriate activation of the renin-angiotensin system is thought to play a role in some forms of human hypertension, adequate vitamin D levels may be important for decreasing the risk of high blood pressure.DeficiencyIn vitamin D deficiency, calcium absorption cannot be increased enough to satisfy the body’s calcium needs (3). Consequently, PTH production by the parathyroid glands is increased and calcium is mobilized from the skeleton to maintain normal serum calcium levels—a condition known as secondary hyperparathyroidism. Although it has long been known that severe vitamin D deficiency has serious consequences for bone health, recent research suggests that less obvious states of vitamin D deficiency are common and increase the risk of osteoporosis and other health problems (17, 18).Severe Vitamin D DeficiencyRicketsIn infants and children, severe vitamin D deficiency results in the failure of bone to mineralize. Rapidly growing bones are most severely affected by rickets. The growth plates of bones continue to enlarge, but in the absence of adequate mineralization, weight-bearing limbs (arms and legs) become bowed. In infants, rickets may result in delayed closure of the fontanels (soft spots) in the skull, and the rib cage may become deformed due to the pulling action of the diaphragm. In severe cases, low serum calcium levels (hypocalcemia) may cause seizures. Although fortification of foods has led to complacency regarding vitamin D deficiency, nutritional rickets is still being reported in cities throughout the world (19, 20).OsteomalaciaAlthough adult bones are no longer growing, they are in a constant state of turnover, or "remodeling." In adults with severe vitamin D deficiency, the collagenous bone matrix is preserved but bone mineral is progressively lost, resulting in bone pain and osteomalacia (soft bones). Muscle Weakness and PainVitamin D deficiency causes muscle weakness and pain in children and adults. Muscle pain and weakness were a prominent symptoms of vitamin D deficiency in a study of Arab and Danish Moslem women living in Denmark (21). In a cross-sectional study of 150 consecutive patients referred to a clinic in Minnesota for the evaluation of persistent, nonspecific musculoskeletal pain, 93% had serum 25(OH)D levels indicative of vitamin D deficiency (22). A randomized controlled trial found that supplementation of elderly women with 800 IU/day of vitamin D and 1,200 mg/day of calcium for three months increased muscle strength and decreased the risk of falling by almost 50% compared to supplementation with calcium alone (23). More recently, a randomized controlled trial in 124 nursing home residents (average age, 89 years) found that those taking 800 IU/day of supplemental vitamin D had a 72% lower fall rate than those taking a placebo (24).Risk Factors for Vitamin D DeficiencyExclusively breast-fed infants: Infants who are exclusively breast-fed and do not receive vitamin D supplementation are at high risk of vitamin D deficiency, particularly if they have dark skin and/or receive little sun exposure (20). Human milk generally provides 25 IU of vitamin D per liter, which is not enough for an infant if it is the sole source of vitamin D. Older infants and toddlers exclusively fed milk substitutes and weaning foods that are not vitamin D fortified are also at risk of vitamin D deficiency (19). The American Academy of Pediatrics recommends that all infants be given a vitamin D supplement of 400 IU/day (20).Dark skin: People with dark-colored skin synthesize less vitamin D on exposure to sunlight than those with light-colored skin (1). The risk of vitamin D deficiency is particularly high in dark-skinned people who live far from the equator. One U.S. study reported that 42% of African American women between 15 and 49 years of age were vitamin D deficient compared to 4% of White women (25).Aging: The elderly have reduced capacity to synthesize vitamin D in skin when exposed to UVB radiation, and the elderly are more likely to stay indoors or use sunscreen, which blocks vitamin D synthesis. Institutionalized adults who are not supplemented with vitamin D are at extremely high risk of vitamin D deficiency (26, 27).Covering all exposed skin or using sunscreen whenever outside: Osteomalacia has been documented in women who cover all of their skin whenever they are outside for religious or cultural reasons (28, 29). The application of sunscreen with an SPF factor of 8 reduces production of vitamin D by 95% (1).Fat malabsorption syndromes: Cystic fibrosis and cholestatic liver disease impair the absorption of dietary vitamin D (30).Inflammatory bowel disease: People with inflammatory bowel disease like Crohn’s disease appear to be at increased risk of vitamin D deficiency, especially those who have had small bowel resections (31).Obesity: Obesity increases the risk of vitamin D deficiency (32). Once vitamin D is synthesized in the skin or ingested, it is deposited in body fat stores, making it less bioavailable to people with large stores of body fat. Assessing Vitamin D Nutritional Statussee the rest of this article at: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/